Durable Responses Achieved With Niraparib and Pembrolizumab Combination for Ovarian Cancer

Panagiotis A. Konstantinopoulos, MD, PhD

Results from a phase I/II trial indicated that durable responses could be achieved with the combination of niraparib (Zejula), a PARP inhibitor, and pembrolizumab (Keytruda), a PD-1 inhbitor, in patients with platinum-resistant/refractory ovarian cancer.

In this trial, 15 evaluable patients out of 60 demonstrated objective responses. In 68% patients in the cohort, disease control (response plus stable disease) was achieved. Analysis of another subgroup demonstrated consistensy in activity across biomarker-selected groups.

Consistency was found in the safety of the combination across the profiles of the individual drugs. There was no new or unexpected toxicities with the combination, according to Panagiotis A. Konstantinopoulos, MD, PhD, who reported these results at the 2018 Society of Gynecologic Oncology Annual Meeting in New Orleans.

“The combination activity was higher than previously reported for single-agent activity of a PARP inhibitor or pembrolizumab,” said Konstantinopoulos, an attending oncologist at Dana-Farber Cancer Institute. “We observed activity in platinum-resistant and platinum-refractory patients and in patients withBRCA-mutated platinum-refractory disease. The combination offers a possible alternative to chemotherapy, and prolonged duration of treatment up to 18 months has been observed.”

There has always been fewer treatment options for patients with recurrent platinum-resistant ovarian cancer. Toxicity increases with combinations including chemotherapy, with no increase in efficacy. The treatment of PARP inhibitors alone has led to objective responses in 25% to 30% of patients whenBRCA-mutant disease is present in the patient. However, this demonstrates limited activity outside of that subgroup, Konstantinopoulos explained. PD-1/PD-L1 inhibitors produce 10% to 15% response rates of, unlike usual responses of PD-L1 expression.

Synergy between PARP inhibitors and anti—PD-1 agents is suggested by recent preclinical models of ovarian cancer, despite BRCA mutation status or PD-L1 expression. To investigate the combination clinically, investigators conducted a phase I/II trial involving patients with platinum-resistant ovarian cancer and triple-negative breast cancer at more than 12 US centers. Konstantinopoulos presented these findings from the ovarian cancer cohort.

Platinum resistance has been defined by the investigators as a response lasting <6 months to the most recent platinum-containing regimen. Patients with primary platinum-refractory disease (progression during or within 1 month of initial platinum therapy) were excluded from the trial, but patients with disease considered platinum refractory in subsequent lines of platinum-based chemotherapy were eligible to move forward. Patients with platinum-sensitive disease were also eligible if they had exhausted all other treatment options. Also, eligible for this treatment were patients who had received as many as 5 prior lines of therapy.

Nine patients were included in phase I of this trial, resulting in recommended phase II doses of 200 mg of niraparib daily and 200 mg every 3 weeks of pembrolizumab. Investigators enrolled an additional 53 patients in phase II of the trial, 2 of which had discontinued after less than 9 weeks without completing any post-baseline scans. Comprehensive biomarker data was also included for 83% of the patients.

Median age of patients was 60 years old, having received a median of 2 therapies prior to this trial. According to Konstantinopoulos, the cohort showed exposure to almost all chemotherapeutic agents used for the treatment of patients with ovarian cancer.

Overall, 11 patients hadBRCAmutations based off the biomarkers, 45 wereBRCAwild-type, and 6 had unknownBRCAstatus. Results were yeilded from testing for homologous recombination deficiency (HRD), resulting positively in 22 patients, negatively in 31, and unknown in 9. The PD-L1 assessment were found positive in 33 patients, negative in 21, and unknown in 9.

In all grades and >20% of patients, the most common adverse events were fatigue, nausea, constipation, anemia, thrombocytopenia, and decreased appetite. The most frequently occurring grade 3/4 adverse events were anemia (19%), thrombocytopenia (9%), decreased platelet count (6%), and fatigue (4%).

The objective response rate across the total of 60 patients was 25% with 2 complete responses. The disease control rate was 68%.

In the analysis of 46 biomarker-selected patients, the combination used in this trial led to objective responses in 2 of 7 patients withBRCAmutations, 4 of 15 who were HRD positive, 9 of 34 who hadBRCAwild-type tumors, and 7 of 24 who were HRD negative.

&ldquo;The addition of pembrolizumab to niraparib inBRCAwild-type and HRD negative patients led to an objective response rate similar to PARP inhibitor efficacy in the BRCA-mutated population.&nbsp;HRD status does not correlate with response to this combination in platinum-resistant or -refractory disease,"&nbsp;said Konstantinopoulos.

Objective responses were found in 24% of 29 patients with platinum-resistant disease and disease control in 72%. The objective response rate was 24% in the 17 patients with platinum-refractory disease while the disease control rate was 59%.

Reference:

Konstantinopoulos PA, Munster P, Forero-Torres A, et al. TOPACIO: preliminary activity and safety in patients (pts) with platinum-resistant ovarian cancer in a phase 1/2 study of niraparib in combination with pembrolizumab. Presented at: SGO Annual Meeting; March 24-27, 2018; New Orleans, LA. Late-breaking abstract.